title: The Batten disease gene CLN3 is required for the response to oxidative stress.
abstract: Mutations in the CLN3 gene cause juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), an early onset neurodegenerative disorder. JNCL is the most common of the NCLs, a group of disorders with infant or childhood onset that are caused by single gene mutations. The NCLs, although relatively rare, share many pathological and clinical similarities with the more common late-onset neurodegenerative disorders, while their simple genetic basis makes them an excellent paradigm. The early onset and rapid disease progression in the NCLs suggests that one or more key cellular processes are severely compromised. To identify the functional pathways compromised in JNCL, we have performed a gain-of-function modifier screen in Drosophila. We find that CLN3 interacts genetically with the core stress signalling pathways and components of stress granules, suggesting a function in stress responses. In support of this, we find that Drosophila lacking CLN3 function are hypersensitive to oxidative stress yet they respond normally to other physiological stresses. Overexpression of CLN3 is sufficient to confer increased resistance to oxidative stress. We find that CLN3 mutant flies perceive conditions of increased oxidative stress correctly but are unable to detoxify reactive oxygen species, suggesting that their ability to respond is compromised. Together, our data suggest that the lack of CLN3 function leads to a failure to manage the response to oxidative stress and this may be the key deficit in JNCL that leads to neuronal degeneration.
authors.affiliation: MRC Centre for Developmental Neurobiology, King's College London, New Hunt's House, Guy's Hospital Campus, London SE1 1UL, UK.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Tuxworth
authors.forename: Haiyang
authors.initials: H
authors.lastname: Chen
authors.forename: Valerie
authors.initials: V
authors.lastname: Vivancos
authors.forename: Nancy
authors.initials: N
authors.lastname: Carvajal
authors.forename: Xun
authors.initials: X
authors.lastname: Huang
authors.forename: Guy
authors.initials: G
authors.lastname: Tear
mesh_terms: D000818:Animals; D004330:Drosophila / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005820:Genetic Testing; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000503:physiopathology*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D010641:Phenotype; D011485:Protein Binding; D014176:Protein Biosynthesis / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D008562:Membrane Glycoproteins; D016877:Oxidants; D017382:Reactive Oxygen Species